Abstract
Muscle disuse leads to a rapid decline in muscle mass, with reduced muscle protein synthesis (MPS) considered the primary physiological mechanism. Here, we employed a systems biology approach to uncover molecular networks and key molecular candidates that quantitatively link to the degree of muscle atrophy and/or extent of decline in MPS during short-term disuse in humans. After consuming a bolus dose of deuterium oxide (D2 O; 3mL.kg-1 ), eight healthy males (22±2years) underwent 4days of unilateral lower-limb immobilization. Bilateral muscle biopsies were obtained post-intervention for RNA sequencing and D2 O-derived measurement of MPS, with thigh lean mass quantified using dual-energy X-ray absorptiometry. Application of weighted gene co-expression network analysis identified 15 distinct gene clusters ("modules") with an expression profile regulated by disuse and/or quantitatively connected to disuse-induced muscle mass or MPS changes. Module scans for candidate targets established an experimentally tractable set of candidate regulatory molecules (242 hub genes, 31 transcriptional regulators) associated with disuse-induced maladaptation, many themselves potently tied to disuse-induced reductions in muscle mass and/or MPS and, therefore, strong physiologically relevant candidates. Notably, we implicate a putative role for muscle protein breakdown-related molecular networks in impairing MPS during short-term disuse, and further establish DEPTOR (a potent mTOR inhibitor) as a critical mechanistic candidate of disuse driven MPS suppression in humans. Overall, these findings offer a strong benchmark for accelerating mechanistic understanding of short-term muscle disuse atrophy that may help expedite development of therapeutic interventions.
Highlights
Reduced physical activity occurring during injury, illness, spaceflight, or with certain lifestyle choices, results in muscle disuse
Periods of short-term muscle disuse occur regularly throughout life and often result in muscle atrophy,[6,7] with the amalgamation of such short periods of muscle disuse regarded as an important driver of sarcopenia.[6]
For the first time, this study combined robust muscle morphological and metabolic (MPS) assessment with data-d riven network analysis to elucidate new mechanistic candidates of short-t erm disuse atrophy in humans, namely by establishing molecular networks and key regulatory molecules quantitatively linked to muscle mass and/or muscle protein synthesis (MPS) changes following 4 days of immobilization
Summary
Reduced physical activity occurring during injury, illness, spaceflight, or with certain lifestyle choices, results in muscle disuse. MPS (both fed and fasted) has been shown to decline with short-term immobilization (5 days) in younger, healthy individuals,[5] while there remains a lack of direct evidence for any quantifiable change in MPB in humans.[14,15] On this basis, attenuated MPS is considered the predominant physiological mechanism of (non-diseased) short-term disuse atrophy[23] and a primary target for therapeutic intervention.[23,24]. Using data obtained as part of a new clinical study of healthy younger volunteers, we combined the above- mentioned bioinformatic and metabolic techniques with robust measures of muscle mass to establish key molecules quantitatively linked to the degree of muscle atrophy and/ or extent of MPS suppression following 4 days of ULLI—in turn providing new insights into possible intrinsic mechanisms of short-term disuse atrophy in humans
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